Hospital mortality and morbidity for some groups of patients undergoing cardiac surgery using cardiopulmonary bypass (CPB) is less than 1%. Thus, CPB seems well tolerated. Yet, as the scope of cardiac surgery extends to ever younger infants and older adults, the probability of observing manifestations of CPB damage increases. These manifestations include a "post perfusion" syndrome, which varies from benign to lethal, characterized by bleeding diatheses, pulmonary and/or renal dysfunction and features reminiscent of acute inflammation: fever, leukocytosis, edema, vasoconstriction, and red cell breakdown. Damaging effects of CPB make postoperative convalescence complex, prolonged, and expensive, and importantly limit the scope of cardiac surgery. Its effects are so powerful that potential benefits of innovations such as pulsatile flow and membrane oxygenation are disappointingly difficult to demonstrate. Our overall goal is to neutralize these damaging effects of CPB. Review of our clinical experiences and synthesis of CPB-related clinical and experimental data with knowledge recently generated in immunology, biochemistry, and cell biology have led us to conclude that there is something fundamental about blood's circulating outside its endotheliatlized channels which initiates a whole body inflammatory response, involving the body's integrated cellular/humoral mechanisms (cross-reacting with the coagulation/fibrinolytic systems) which are normally functional only at local sites of injury. Heretofore, this response could be studied only in a limited way. We propose to combine the unique ability of molecular and cellular immunologists to now directly measure some of these phenomena, with our ability to relate this objective information to clinical observations made through long-experienced eyes. We will measure the presence, pattern, and levels of humoral and cellular mediators of inflammation (particularly of complement-derived anaphylatoxins), establish their clinical importance using multivariate statistical analyses, and test modalities to neutralize their effects. The studies involve in vitro, experimental animal, and clinical studies carried out collaboratively and in parallel at the primary institution and in the Department of Molecular Immunology at Scripps Clinic and Research Foundation in an attempt to increase the safety of CPB, and the scope of cardiac surgery, at reduced costs.